Calorie restriction (CR) delays age-related diseases in laboratory animals, and a small molecule or behavioral intervention that safely mimics its effects has been greatly sought after. RESVERATROL: There is evidence that resveratrol can mimic effects of CR in lower organisms and we have now concluded the first study of the aging intervention program. In mice, we found that resveratrol induces gene expression patterns in multiple tissues that are highly similar to those induced by CR. Moreover, elderly resveratrol-fed mice showed a marked reduction in signs of aging. These changes included reduced albuminuria, decreased inflammation and apoptosis in the vascular endothelium, increased aortic elasticity, greater motor coordination, reduced cataract formation, and preservation of bone mineral density. However, mice fed a standard diet did not live longer when treated with resveratrol beginning at mid-life. Thus it is possible to mimic transcriptional aspects of DR and delay functional decline with a safe, orally available small molecule. Our findings indicate that resveratrol treatment starting from mid-life has a range of beneficial effects in mice, but suggest that it may not be an effective strategy to increase the longevity of normal ad libitum-fed animals. Long-term resveratrol treatment mimicked important physiological and transcriptional aspects of CR in vivo, and allowed treated animals to live healthier, more vigorous lives. In addition to improving insulin sensitivity and increasing survival in mice fed a high calorie diet, we found evidence that resveratrol improves cardiovascular function, bone density, motor coordination, and delays cataracts, even in non-obese rodents. Since cardiovascular disease is a major cause of age-related morbidity and mortality in humans but not mice, it is possible that a CR mimetics such as resveratrol could have an even greater impact on human health than on mice. However, resveratrol does not seem to mimic all of the salutary effects of DR in that its introduction into the diet of normal one year old mice did not increase longevity. When we tested resveratrol in non-human primates we were able to replicate most of the findings in rodents. For example, in a manuscript under review, we tested the effect of a 2-year resveratrol administration on the pro-inflammatory profile and insulin resistance caused by a high-fat, high-sugar (HFS) diet in white adipose tissue (WAT) from rhesus monkeys. Eighty mg/day of resveratrol for 12-month followed by 480 mg/day for the second year decreased adipocyte size, increased sirtuin 1 expression, decreased NF-kB activation and improved insulin sensitivity in visceral but not subcutaneous WAT from HFS-fed animals. These effects were reproduced in 3T3-L1 adipocytes cultured in media supplemented with serum from monkeys fed HFS +/- resveratrol diets. In conclusion, chronic administration of resveratrol exerts beneficial metabolic and inflammatory adaptations in visceral WAT from diet-induced obese monkeys. METFORMIN: Another CR mimetic compound that we have tested is metformin. Metformin, a drug commonly prescribed to treat type-2 diabetes. We showed that treatment with metformin (0.1% w/w in diet) starting at one year of age extends healthspan and lifespan in male mice, while a higher dose (1% w/w) was toxic. Treatment with metformin mimicked some of the benefits of calorie restriction, such as improved physical performance, increased insulin sensitivity, and reduced LDL and cholesterol levels without a decrease in caloric intake. At a molecular level, metformin increased AMP-activated protein kinase activity and increased antioxidant protection, resulting in lower oxidative damage accumulation and chronic inflammation. Our results indicate that these specific factors may contribute to the beneficial effects of metformin administration on healthspan and lifespan. These findings are in agreement with current epidemiological data and further support metformin-based interventions to promote healthy aging. EXCERCISE: The current literature in exercise studies show variable results based on multiple confounders, such as intensity and duration of exercise, type of exercise (voluntary or forced), gender, and age of onset. However, there is a general consensus regarding the benefits of exercise for promoting healthy aging (increases in mean lifespan) due to modulations in parameters, such as glucose and lipid metabolism, insulin sensitivity, and mitochondrial function. Despite the published benefits of exercise on metabolism, there are no conclusive or comprehensive studies outlining the effects of exercise on increased survival. This research aims to investigate the role of daily exercise on health, metabolism, and survival in young and old male and female mice. We will investigate the underlying mechanisms through which exercise exerts its effects and determine if age of onset and sex affect outcomes. Understanding the underlying mechanisms through which exercise benefits health will allow us to develop effective models for translation to humans. We hypothesized that daily exercise would favor metabolic changes that will ameliorate age-dependent decline in physiology, motor function and cognition, therefore improving both mean and maximal lifespan. METFORMIN + EXCERCISE: We are working to optimize the feeding protocol with 0.5% metformin that will improve healthspan and promote life extension in mice, and that alternating metformin supplementation with brisk exercise will have the capacity to enhance skeletal muscle structure and function. The proposal is divided in two specific aims: In the first AIM, 12 month-old C57BL/6J mice will be fed or not with 0.5% metformin every-other-week (EOW) to ascertain whether the course of aging will be altered. The second AIM of the study is to determine the relative contribution of 0.5% metformin added alone or combined with exercise in the modulation of autophagy and mTORC1 signaling pathways in mouse skeletal muscle.